Abstract The Problem: Antibiotic resistance is a serious and increasing threat to public health. The RFA that prompts our proposal encourage ?Modulation of host immune response to combat infection and/or reduce disease pathology.? The Proposed Solution: We focus on one specific candidate immunomodulator, plasma gelsolin (pGSN) which will benefit patients with antibiotic- resistant bacterial pneumonias (ARPs) by three distinct mechanisms: 1) enhanced macrophage bacterial killing; 2) clearance of extracellular actin released by lung injury (which inhibits bacterial clearance); and 3) binding/dampening excess pro-inflammatory mediators. Diminished pGSN in blood predicts poor outcome in critically ill patients, and restoration in animal models allows survival from otherwise fatal injuries. This has led to already completed, extensive safety and toxicity evaluation of pGSN as a possible therapeutic for other clinical problems. This groundwork provides a strong start for the main goal of this project: to assess and optimize use of plasma gelsolin (pGSN) as a broad-spectrum immunomodulator to improve treatment of antibiotic-resistant bacterial pneumonias ARPs. The Plan: Aims 1 and 2 will test pGSN for improved outcome in primary and secondary ARP mouse models (Strep. pn, MRSA, and Pseudomonas). We will test post-infection efficacy, alone or in combination with suboptimal antibiotics, analyze drug levels, inflammatory and pathologic parameters in optimized protocols, and compare systemic vs. aerosol delivery routes. Aim 3 will develop a clinical testing ELISA assay for use in human studies. Product development efforts will address formulation, safety and regulatory issues needed to expedite clinical testing upon completion. The Significance & Impact: pGSN is a novel, host-targeted therapeutic that has already passed many safety and regulatory hurdles for clinical use. We expect that this project will establish its utility for infections caused by multiple pathogens, and expedite its translation into the clinic for the growing problem of antibiotic ?resistant pneumonia.